Bladder Voiding via Pudendal Nerve Block - Project Summary/Abstract Objectives and Research Aims: Bladder dysfunction after neurological injury or disorders such as spinal cord injury (SCI), brainstem stroke, and multiple sclerosis can have a devastating impact on patients and their families, resulting in a high cost to the individual and to society. The long-term goal of this research program is to develop neural prostheses to restore complete lower urinary tract function in persons with neurological disorders;particularly SCI. These disorders can result in reflex urethral sphincter activity that can prevent voiding and lead to renal damage and autonomic dysreflexia. Surgical section of the urethral sphincter or the pudendal nerves that innervate the sphincter can reduce these complications but may result in loss of urinary and fecal continence, sexual function and sensation. Research Design and Methods: This study proposes a new approach utilizing high frequency (HF) electrical conduction block of the pudendal nerves to produce bladder voiding. Electrical nerve block provides an immediate, reversible approach to block action potential propagation. During our current Merit Review we have demonstrated that HF electrical block of the pudendal nerves, and thereby the external urethral sphincter (EUS) during bladder activation can produce bladder voiding equivalent to pudendal nerve transection. These results demonstrate that electrical nerve block can restore voiding function in acute animal experiments and that a neural prosthesis using pudendal nerve block is feasible. This proposal will conduct the studies needed to translate these results into clinical implementation. Specifically, we will determine the chronic efficacy and safety of this approach to produce voiding in chronic SCI animals that demonstrate bladder-sphincter dyssynergia similar to humans with SCI. Nerve cuff electrodes will be placed on the pudendal nerves to allow HF block of the urethral sphincter, and on the sacral roots to allow bladder drive in animals. Stimulus parameters for effective nerve block and voiding efficacy will be monitored for 8 weeks. Animals that demonstrate stable and effective pudendal HF block and voiding will be spinalized. The implanted electrodes will then be used for voiding;therefore the implanted system will be the primary means of managing bladder function in these animals. The effectiveness of combined pudendal HF pudendal block and sacral root activation to provide bladder emptying will be determined. Nerve function and histological measures will be used to determine the neural tissue responses to the chronic HF waveforms. Clinical Significance: Successful completion of this project will take an important step towards translating our recent advances discovered in animal models to veterans with SCI. This will support future human feasibility testing of an implanted neural prosthesis able to restore bladder function. This approach is expected to expand the population of individuals who could benefit from neural prostheses to control the bladder, and thereby improve their health and quality of life while reducing costs to the healthcare system. This project will also improve our understanding of HF block that can be expanded to other medical applications such as chronic pain, muscle spasticity in stroke and cerebral palsy. PUBLIC HEALTH RELEVANCE: Bladder Voiding via Pudendal Nerve Block - Project Narrative Relevance of Proposed Work to Veterans Health This work is directly applicable to the health, well-being, and functional independence of disabled veterans. Although about 9% of Americans are veterans, they comprise over 17% of all individuals with spinal cord injuries in the United States. In addition to being a debilitating and costly condition, paralysis compromises the ability to work, engage in social or leisure activities, pursue an education, or participate in other activities associated with an independent and productive lifestyle. SCI and other disabilities causing neurogenic bladder, such as multiple sclerosis and stroke, lead to urological complications, such as incontinence, urinary tract infection, renal damage and consequent renal dialysis or transplantation can lead to recurrent and costly hospitalization. This project directly addresses the urologic complications experienced by veterans with SCI or neurological disorders by providing a means to produce on-demand bladder emptying. Successful completion of this study will provide data required to translate this approach to clinical implementation and lead to the development of an effective neural prosthesis to restore bladder function. In addition, the substantial potential future clinical impact from HF nerve block to a number of other clinical applications, such as chronic pain, muscle spasticity, etc. increases the value of this work.